Dataset Information

Frequency of the loss of CAA interruption in the HTT CAG tract and implications for Huntington disease in the reduced penetrance range.

ABSTRACT: Purpose: In some Huntington disease (HD) patients, the "loss of interruption" (LOI) variant eliminates an interrupting codon in the HTT CAG-repeat tract, which causes earlier age of onset (AOO). The magnitude of this effect is uncertain, since previous studies included few LOI carriers, and the variant also causes CAG size misestimation. We developed a rapid LOI detection screen, enabling unbiased frequency estimation among manifest HD patients. Additionally, we combined published data with clinical data from newly identified patients to accurately characterize the LOI's effect on AOO.

Methods: We developed a LOI detection polymerase chain reaction (PCR) assay, and screened patients to estimate the frequency of the LOI variant and its effect on AOO.

Results: Mean onset for LOI carriers (n?=?49) is 20.4 years earlier than expected based on diagnosed CAG size. After correcting for CAG size underestimation, the variant is still associated with onset 9.5 years earlier. The LOI is present in 1.02% of symptomatic HD patients, and in 32.2% of symptomatic reduced penetrance (RP) range patients (36-39 CAGs).

Conclusion: The LOI causes significantly earlier onset, greater than expected by CAG length, particularly in persons with 36-39 CAG repeats. Detection of this variant has implications for HD families, especially for those in the RP range.

SUBMITTER: Findlay Black H

PROVIDER: S-EPMC7708297 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Frequency of the loss of CAA interruption in the HTT CAG tract and implications for Huntington disease in the reduced penetrance range.

Findlay Black Hailey H Wright Galen E B GEB Collins Jennifer A JA Caron Nicholas N Kay Chris C Xia Qingwen Q Arning Larissa L Bijlsma Emilia K EK Squitieri Ferdinando F Nguyen Huu Phuc HP Hayden Michael R MR

Genetics in medicine : official journal of the American College of Medical Genetics 20200803 12

<h4>Purpose</h4>In some Huntington disease (HD) patients, the "loss of interruption" (LOI) variant eliminates an interrupting codon in the HTT CAG-repeat tract, which causes earlier age of onset (AOO). The magnitude of this effect is uncertain, since previous studies included few LOI carriers, and the variant also causes CAG size misestimation. We developed a rapid LOI detection screen, enabling unbiased frequency estimation among manifest HD patients. Additionally, we combined published data wi ...[more]

PMID: 32741964

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Dataset Information

Frequency of the loss of CAA interruption in the HTT CAG tract and implications for Huntington disease in the reduced penetrance range.

Publications

Frequency of the loss of CAA interruption in the HTT CAG tract and implications for Huntington disease in the reduced penetrance range.

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